This invention relates to a process for making spiro isobenzofuranone compounds, in particular 2-oxo-N-(5-phenylpyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide by coupling of an aminopyrazine fragment with a spirolactone piece.
For the aminopyrazine fragment, the process in this invention involves a selective monobromination, a catalyzed Suzuki coupling and carbamate formation steps. The synthesis of the spirolactone piece involves lithiation/addition to 1-benzyl-4-piperidone, acid catalyzed cyclization and deprotection by hydrogenolysis. Prior to the present invention, the monobromination of 2-aminopyrazine would produce a low yield of the desired product due to side reactions. However, the use of a flow-cell type reactor in the present invention significantly improves the yield. During the Suzuki coupling, the addition of a stable crystalline solid catalyst with reliable quality improves the coupling. In addition, the present invention provides an environmentally sound process that eliminates the need to use pyridine as the solvent during the carbamate formation and chloroform in the final coupling. As a result, the present invention provides an environmentally sound procedure for making functionalized pyrazine compound in good yields.